Circadian rhythms are fundamental components of animals' adaptation to their environment. They provide a precise temporal organization of physiological and behavioral processes that is essential to survival. In mammals, circadian rhythms are generated by a circadian timing system (CTS) which contains a pacemaker, the suprachiasmatic nucleus of the hypothalamus (SCN) with its efferent projections and two visual entraining pathways, the retinohypothalamic tract (RHT) and the geniculohypothalamic tract (GHT). Disorders of the CTS are observed in sleep disorders, affective disorders, neuroendocrine diseases and ageing. The proposed research will analyze the functional organization of each component of the CTS. This will include a detailed analysis of retinal ganglion cells projecting to the SCN, and the source of the GHT, the intergeniculate leaflet (IGL). The IGL will be characterized morphologically and its afferent and efferent connections will be determined. we will attempt to determine the transmitters utilized by the RHT and GHT. The function of the GHT will be analyzed by measuring neuropeptide Y and enkephalin content and message level in the IGL, and SCN where appropriate, at different times of the circadian day. The function of entraining pathways will be analyzed by determining the phase the firing rate rhythm from single unit recordings from SCN in response to pharmacological treatments. The organization efferent projections of the SCN, particularly to the retrochiasmatic and subparaventricular areas, will be analyzed using retrograde transport, anterograde transport and immunocytochemistry. The functional relations between the CTS and effector systems expressing circadian function will be studied using transplants of fetal hypothalamic tissue. The objective is to determine what components of the SCN are required to restore function, what connections between host and graft are required and whether there is any specificity between graft content, location or connections and the type of circadian function that is restored.